INT230-6 monotherapy and in combination with ipilimumab (IPI) across a broad spectrum of refractory soft tissue sarcomas (STS) [Intensity IT-01; BMS#CA184-592].
Authors: Matthew Ingham, James S Hu, Giles Francis Whalen, Jacob Stephen Thomas, Anthony B. El-Khoueiry, Diana L. Hanna, Anthony J. Olszanski, Christian Frederick Meyer, Nilofer Saba Azad, Luis H. Camacho, Syed Mahmood, Lewis H. Bender, Ian B. Walters, Lillian L. Siu, Albiruni Ryan Abdul Razak
Journal: Journal of Clinical Oncology (2022)

11515 Background: INT230-6 is a novel intratumoral (IT) agent with a dual anti-cancer mechanism (tumor cytoreduction while stimulating antigen presentation and recruitment of T-cells). The drug is comprised of cisplatin (CIS) and vinblastine (VIN) co-formulated with an amphiphilic molecule that enables drug dispersion throughout tumors and passive diffusion into cancer cells following IT delivery. In the neoadjuvant setting, a single injection can cause necrosis in &gt; 95% of the tumor and recruit TILs. Combining with anti-CTLA-4 improved responses in preclinical models. Methods: INT230-6 dose is set by the tumor’s longest diameter and is proportional to the injected disease volume. INT230-6 is administered IT Q2W for 5 treatment sessions followed by maintenance every 9 weeks as monotherapy or with IPI 3mg/kg IV Q3W for 4 doses. Biopsies from injected tumors are obtained pretreatment and Day 28 for immunoprofiling. Results: 22 subjects with various advanced STS histologies with a median age of 64 and a median of 3 prior systemic therapies were enrolled (11 INT230-6 alone, 11 IPI combination). There were 178 image-guided IT INT230-6 injections (107 to deep tumors) at INT230-6 doses ranging from 5 to 242 mL (121mg CIS, 24.2mg VIN, doses which vastly exceed the usual IV doses of these drugs). PK analysis showed that &gt; 95% of drug agents remain in the tumor. The most common (&gt; 25%) all-grade related adverse events (AEs) in evaluable monotherapy subjects (n = 10) were pain (80%), decreased appetite (40%), nausea (40%), anemia (30%), fatigue (30%) and vomiting (30%). Tolerability was similar for the combination with IPI. Most events were low grade. The incidence of grade 3 AEs for the INT230-6 arm was 30% and for the IPI combination was 10%. There were no related grade 4 or 5 AEs in either cohort. RECIST metrics may not accurately reflect clinical benefit with this treatment given large volumes of INT230-6 is repeatedly injected into a tumor and local inflammation may occur. Paired biopsies showed reduction in proliferating tumor cells and an increase in T-cell infiltrates. The disease control rate at the first imaging timepoint for evaluable INT230-6 subjects (n = 9) was 56% and for evaluable IPI combination (n = 5) was 80%. Abscopal effects were seen in 2 monotherapy subjects, though most uninjected tumors were not tracked. The estimated 1-year overall survival was 88% for the IPI combo and 60% for the monotherapy cohort. Conclusions: IT INT230-6 is well tolerated as monotherapy and combined with IPI. STS, which is typically not sensitive to immunotherapy, may be amenable to INT230-6 or IPI combo to create antigens and promote a systemic immune response. Preliminary efficacy using INT230-6 alone is encouraging and will be evaluated in a global phase 3 trial. Further evaluation is needed to determine whether the addition of IPI may improve patient outcomes. Clinical trial information: NCT03058289.